Primary cutaneous T-cell lymphomas (CTCL) represent a group of malignancies of mature T lymphocytes, which show a homing preference for skin. CTCL most often occurs in people aged between 40 and 60 and the two major clinical variants of CTCL are mycosis fungoides (MF) or Sezary syndrome (SzS).
Mycosis fungoides (MF), the most common type of CTCL, presents with skin lesions showing epidermotrophic clonal T lymphocytes (Willemze R et al. Blood 90:354-371, 1997). CTCL may also present in a leukaemic form with erythrodermic skin involvement and lymphadenopathy (Sezary syndrome, SzS), and 10-20% of MF cases transform to large T-cell lymphoma with time (Willemze R et al. Blood 90:354-371, 1997, Willemze R et al. Blood 105:3768-3785, 2005). Ten-year relative survival of MF, the most benign form of the cutaneous T-cell lymphomas ranges from 100% to 41%, depending on the degree of skin involvement. Patients with SzS have a prognosis with an estimated 5-year survival of 15% (Willemze R et al. Blood 90: 354-71, 1997). Therefore, many patients with advanced disease do not respond to therapy and furthermore, many patients having some response to therapy will later suffer a relapse. Thus, there is an urgent need for life-saving therapeutics.
The molecular mechanisms leading to CTCL are still largely unknown. Previously performed microarray studies have found no uniform gene expression signatures (Kari L et al. J Exp Med 197:1477-1488, 2003, van Doorn R et al. Cancer Res 64:5578-5586, 2004, Tracey L et al. Blood 102:1042-1050, 2003), most likely due to a wide range of different experimental designs and microarray platforms used. On one hand, an expression profile suggesting upregulation of genes involved in TNF signaling pathway was found among MF skin samples (Tracey L et al. Blood 102:1042-1050, 2003). On the other hand, among SzS samples, many Th2-specific transcription factors (like Gata-3 and JunB) were found overexpressed, while underexpressed genes included CD26, Stat4, and IL-1 receptors in one study (Kari L et al. J Exp Med 197:1477-1488, 2003) and decreased expression of some tumor suppressor genes such as TGF-β receptor 11 with overexpression of EphA4 and Twist in an other study (van Doorn R et al. Cancer Res 64:5578-5586, 2004). Due to the different probe and sample sets, and to the lack of publicly available raw data of array hybridizations, comparison of the published data is difficult. Recently, the very low concordance in array profiles obtained with the same samples on different devices has been clearly demonstrated (Tan P K et al. Nucleic Acids Res 31:5676-5684, 2003, Marshall E. Science 306:630-631, 2004). To get a better comprehension of CTCL pathogenesis, we analyzed fresh cells from various tissues of both SzS and MF, and compared their expression profiles with DNA copy number data, since DNA copy number changes contribute to variation in gene expression (Pollack J R et al. Proc Natl Acad Sci USA 99:12963-12968, 2002).
Helper T (Th) cells are essential for developing an immune response by activating antigen-specific effector cells and recruiting cells of the innate immune system such as macrophages and mast cells. Th1 commitment relies on the local production of IL-12, and Th2 development is promoted by IL-4 in the absence of IL-12. Th1 cells participate in cell-mediated immunity and control intracellular pathogens. The cytokines produced by Th1 cells stimulate phagocytosis and destruction of microbial pathogens. Th2 cells are essential for antibody-mediated immunity by stimulating the production of antibodies. Thus, Th2 cells participate in controlling extracellular pathogens. Excessive Th1 responses are involved in many autoimmune diseases, whereas excessive Th2 responses are known to lead for example to chronic diseases, including allergies, asthma, and chronic bronchitis. Increased Th2 cytokine levels have also been revealed in various malignancies including CTCL (Kari L et al. J Exp Med 197:1477-1488, 2003).
Profound understanding of CTCL improves the possibilities of diagnosing or curing the disease. None of the previous documents describes CTCL specific genes or gene products presented in this patent application (Kari L et al. J Exp Med 197:1477-1488, 2003, van Doorn R et al. Cancer Res 64:5578-5586, 2004, Tracey L et al. Blood 102:1042-1050, 2003, and US2005074761). Therefore, this invention provides novel tools for CTCL diagnostics and therapeutics.